The purpose of this project is to determine whether human papilloma virus (HPV) infection is associated with oral cancer in the elderly. We will identify HPV frequency (+/-) and types in exfoliative cytology samples from 1) newly diagnosed cases with oral cancer (ICD-O: 140-146; n=333), 2) cases with leukoplakia (n=400), which condition is generally benign but in some cases progresses to oral cancer (2-8% progress), and 3) controls with clinically normal oral tissue (n=333). Cancer cases will include all those who are identified during a four-year period from the university hospital and local VAMC and an age-sex-frequency matched control group identified from the same population sources. Demographic, histopathologic, extent of disease, and survival characteristics will be compared with that of the NCI-Iowa SEER Cancer Registry for bias and generalizability of results. Four types of data will be collected for each patient: 1) HPV DNA tests of positivity and types, 2) cytology/pathology report, 3) patient questionnaire about risk factors and confounders, and 4) medical/dental history. HPV types will be identified using the polymerase chain reaction, hybridizing and radioactive probes for HPV types 2,6,11,16,18,31,33,35,42,45,51,52,54,58 and other types potentially related to this mucosa disease. We will compare the frequency of HPV infection and types in controls with clinically normal oral tissues to that of cases having either benign (leukoplakia) or malignant lesions (oral cancer). Multivariate analyses will be used to control for confounders, and to examine independent and interaction effects of risk factors, particularly HPV frequency/types associated with age, smoking, and alcohol, to determine whether HPV is an important risk in many or specific patient populations, such as those who are not exposed to the traditional risk factors. HPV infected oral cancer and leukoplakia biopsy tissues will be evaluated for integration patterns to elucidate its role as a mechanism in the pathway of progression malignancy. The purpose of the molecular assessment of these specimens is to be able to characterize HPV integration patterns for the loss of the E1/E2 genes and deregulation of the E6-E7 oncogenes. This study is to collaborative effort between clinical, epidemiology, and molecular biology colleagues to evaluate the etiology of oral cancer using different approaches to study the disease in the same patient study group. The clinical diagnosis will be examined in light of the epidemiologic and molecular findings for insights into early screening procedures and cancer detection. Differences in HPV characteristics in conjunction with other oral cancer risks may predict individuals who are at higher risk for developing malignancy and thus, suggest in whom cytologic screening for HPV should be performed. Results also will extend our understanding of the role of HPV in the development of cancer.